Glioblastoma multiforme (GBM) is a complex and heterogeneous disease, with prevalent short-term relapse and a median survival time of about 1 year when treated with surgery, radiotherapy and temozolomide [1-3]. Categorization by transcriptional clustering into proneural (better patient survival profile), indeterminant (“neural”), mesenchymal (associated with NF-1 loss) and proliferative (“classical”; associated with EGFR mutation or amplification) subtypes (reviewed in [1]) has underscored the usefulness of individualized patient profiles in determining prognosis as well as rational selection of targeted therapeutics, however a practical approach to targeting these subtypes clinically needs to be developed.
Despite intensive radio- and chemotherapy, tumor regrowth is virtually inevitable and typically occurs within a few centimeters of the resection margin [4]. There are two potential disease reservoirs that may contribute to treatment failure. First, invasive glioma has been characterized by recent clinical and in vitro studies which have shown that genetically and phenotypically distinct cells can form long tendrils which extend several centimeters away from the main tumor mass, or form diffusely spread, invasive subpopulations of tumor that are resistant to chemo- and radiotherapy, by virtue of their remote localization from the main tumor site [4-6], as well as expression of drug resistance genes and enhanced DNA repair capabilities [7-10]. These cells are referred to herein as highly invasive glioma cells, or HIGC's.
The second putative reservoir is based on concept of Cancer Stem Cells (CSCs), which arose because mechanisms of self-renewal without terminal differentiation were similar between stem cells and cancer cells [11]. The cancer stem cell hypothesis proposes that a rare population of transformed stem cells, or progenitor cells with acquired self-renewal properties are the source of tumor cell renewal. Evidence for the existence of cancer stem cells has been suggested for a number of hematological malignancies [12-14] and more recently for a number of solid tumors [14-18].
There is now accumulating in vitro and in vivo data supporting the involvement of CSCs in glioblastoma [19-25]. The concept of brain tumor stem cells, or as they are referred to herein, as brain tumor-initiating cells or BTICs, is potentially important since they would define a tumor's behavior including proliferation, progression and response to therapy. One of the most important features of BTICs is that they closely resemble the human disease and therefore may be the best system for understanding brain tumor biology and developing therapeutics [23]. In addition, BTICs have fewer cytogenetic and molecular abnormalities [21, 23], which should make identifying causal events (i.e. instead of changes which occur as a consequence of transformation) in brain tumor formation easier. It should be clearly stated that the presence of a BTIC and the exact operational definition and use of terminology is a topic of great debate. As CD133 is controversial as an indicator of “stemness”[26-28], it is proposed herein that BTICs be defined as patient-derived cells with the ability to self-renew, differentiate into multiple lineages and form tumors in vivo [28].